The consistent deletion of 3p21 in
lung cancer has led to intensive efforts to identify a lung tumor suppressor gene at this locus. We recently mapped the gene for the
selenium-dependent
drug-detoxifying
enzyme glutathione peroxidase 1 (GPX1) to this location by in situ hybridization. We developed a polymerase chain reaction-based assay which demonstrated the existence of three GPX1 alleles characterized by the number of alanines in a
polyalanine coding sequence in exon 1. These three alleles produced a heterozygote frequency of 70% in two separate populations: normal tissue
DNA taken from Centre d'Etude du Polmorphisme Humain (CEPH) parents and normal tissue taken from
cancer patients. In contrast, 10 heterozygote
tumors were detected out of 64
lung cancer specimens. Linkage analysis of GPX1 to Genethon 3p markers in CEPH pedigrees demonstrated that GPX1 was located between the two microsatellite markers believed to flank the
lung cancer deletion site. Nucleotide sequence analysis of GPX1 alleles did not reveal any mutations of this gene in lung
tumors. However, sequence analysis did reveal that the three GPX1 alleles were characterized by three
nucleotide substitutions in addition to the
polyalanine polymorphism, including a substitution at
codon 198 which results in either a
proline or
leucine at that position. Therefore, the different GPX1 alleles encode structurally different hGPx1 subunits. In addition, analysis of allele frequency suggests that the GPX1*ALA7 allele may occur less frequently in
tumors with 3p21 deletions.